Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase ( <i>IDH</i> ) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of <i>Gsx2</i> , a homeobox gene required for neurogenesis. Critically, <i>Gsx2</i> ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by <i>IDH</i> oncogenes and insights into the developmental origins of glioma.